Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase

作者：Iyidogan Pinar; Sullivan Todd J; Chordia Mahendra D; Frey Kathleen M; Anderson Karen S^*

来源：ACS Medicinal Chemistry Letters, 2013, 4(12): 1183-1188.

DOI：10.1021/ml4002979

• HIV
• reverse transcriptase
• nucleoside H-phosphonate
• NNRTI
• synthesis

In a continuing study of potent bifunctional anti-HIV agents, we rationally designed a novel chimeric inhibitor utilizing thymidine (THY) and a TMC derivative (a diarylpyrimidine NNRTI) linked via a polymethylene linker (ALK). The nucleoside, 5'-hydrogen-phosphonate (H-phosphonate), and S'-triphosphate forms of this chimeric inhibitor (THY-ALK-TMC) were synthesized and the antiviral activity profiles were evaluated at the enzyme and cellular level. The nucleoside triphosphate (11) and the H-phosphonate (10) derivatives inhibited RT polymerization with an IC50 value of 6.0 and 4.3 nM, respectively. Additionally, chimeric nucleoside (9) and H-phosphonate (10) derivatives reduced HIV replication in a cell-based assay with low nanomolar antiviral potencies.

• 出版日期2013-12